E2F is a family of transcription factors implicated in a variety of cell fates including proliferation, apoptosis and differentiation (Stevens and La Thangue; 2003; Frolov and Dyson 2004, Polager and Ginsberg 2008; van den Heuvel and Dyson 2008). E2F proteins share the capacity to regulate a diverse group of target genes (Frolov and Dyson 2004; van den Heuvel and Dyson 2008). The first family member identified, E2F-1, physically interacts with the retinoblastoma tumour suppressor protein pRb, which negatively regulates E2F-1 activity (Bandara and La Thangue 1991; Zamanian and La Thangue 1992; Weinberg 1995; Stevens and La Thangue 2003). Whilst it is established that E2F-1 can promote proliferation, it has also become clear that E2F-1 can prompt apoptosis (van den Heuvel and Dyson 2008, Polager and Ginsberg 2008). In Rb−/− mice, the enhanced levels of apoptosis in certain tissues reflect deregulated E2F-1 activity (Tsai et el 1998; Iaquinta and Lees 2007). Further, E2F-1−/− mice suffer from an increased incidence of tumours (Field et al 1996), suggesting that E2F-1 adopts a tumour suppressor role in some tissues, perhaps reflecting its ability to induce apoptosis. However, the mechanisms that influence the diverse cellular outcomes that have been ascribed to E2F-1 activity, particularly its apoptotic activity and the cell context dependency of these events, remain elusive. It is an object of the invention to identify such mechanisms. Not only is E2F-1 regulated during cell cycle progression (Stevens and La Thangue, 2003, van den Heuvel and Dyson 2008), but also under conditions of DNA damage (Pediconi et al 2003; Stevens et at 2003; Stevens and La Thangue 2003). In DNA damaged cells, E2F-1 is induced in a fashion that follows similar kinetics to p53 (Pediconi et al 2003; Stevens and La Thangue 2003), which co-incides with activation of a diverse collection of E2F target genes (Ren et al 2002). DNA damage activates a signal transduction pathway involving protein phosphokinases, such as ATM/ATR and Chk1/Chk2, which in turn phosphorylate effector proteins that mediate the outcome of the DNA damage response (Jackson and Bartek, 2009). Both families of DNA damage responsive kinases phosphorylate E2F-1, which contributes to the regulation of E2F-1 in DNA damaged cells (Stevens et al 2003; Stevens and La Thangue 2003). Moreover, E2F-1 prompts apoptosis under DNA damage conditions and, in tumour cells which harbour compromised p53 activity, might provide an important pathway that enables apoptosis to be activated (Stevens and La Thangue 2003).
Arginine methylation is established as an important type of modification in protein control (Bedford and Richard 2005). A variety of processes are influenced by arginine methylation, including RNA splicing, chromatin and transcription control (Meister et al 2001; Pal et al 2004; Bedford and Richard 2005). It has been established that the p53 tumour suppressor protein is regulated by arginine methylation, and defined a role for the protein arginine N-methyltransferase 5 (PRMT5) (Janson et al 2008). Significantly, arginine methylation occurred in DNA damaged cells, and influenced the outcome of the p53 response (Janson et al 2008).
Cancer (and other hyperproliferative disease) is characterised by uncontrolled cellular proliferation. It is an object of the present invention to provide an alternative strategy for treating cancer and other proliferative diseases. Specifically it is an object of the invention to identify mechanisms that may be manipulated to lead to the death of tumour cells and other cells that proliferate abnormally. It is a further object of the invention to provide screening methods for identifying compounds that may be useful in the treatment of these conditions. It is a further object of the invention to identify a biomarker to identify responsive tumours.